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Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity.
Clin Cancer Res 2016; 22(20):5130-5140CC

Abstract

PURPOSE

Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions.

EXPERIMENTAL DESIGN

We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632).

RESULTS

Osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [11C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11C]rociletinib and [11C]gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported.

CONCLUSIONS

Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing. Clin Cancer Res; 22(20); 5130-40. ©2016 AACR.

Authors+Show Affiliations

iMED Oncology, AstraZeneca, Macclesfield, United Kingdom. Darren.Cross@astrazeneca.com pbdmpk@gmail.com.iMED Oncology, AstraZeneca, Cambridge, United Kingdom.Asia and Emerging Markets iMED, AstraZeneca, Shanghai, China.Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.National Taiwan University Hospital, Taipei City, Taiwan.Global Medicines Development, AstraZeneca, Macclesfield, United Kingdom.iMED Oncology, AstraZeneca, Macclesfield, United Kingdom.iMED Oncology, AstraZeneca, Macclesfield, United Kingdom.AstraZeneca, Cambridge, United Kingdom.iMED Oncology, AstraZeneca, Macclesfield, United Kingdom.iMED Oncology, AstraZeneca, Macclesfield, United Kingdom.AstraZeneca Translational Science Centre, Stockholm, Sweden. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.iMED Oncology, AstraZeneca, Gatehouse Park, Waltham, Massachusetts.Dana-Farber Cancer Institute, Boston, Massachusetts.iMED Oncology, AstraZeneca, Cambridge, United Kingdom. Darren.Cross@astrazeneca.com pbdmpk@gmail.com.

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

27435396

Citation

Ballard, Peter, et al. "Preclinical Comparison of Osimertinib With Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 22, no. 20, 2016, pp. 5130-5140.
Ballard P, Yates JW, Yang Z, et al. Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016;22(20):5130-5140.
Ballard, P., Yates, J. W., Yang, Z., Kim, D. W., Yang, J. C., Cantarini, M., ... Cross, D. (2016). Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 22(20), pp. 5130-5140.
Ballard P, et al. Preclinical Comparison of Osimertinib With Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016 Oct 15;22(20):5130-5140. PubMed PMID: 27435396.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. AU - Ballard,Peter, AU - Yates,James W T, AU - Yang,Zhenfan, AU - Kim,Dong-Wan, AU - Yang,James Chih-Hsin, AU - Cantarini,Mireille, AU - Pickup,Kathryn, AU - Jordan,Angela, AU - Hickey,Mike, AU - Grist,Matthew, AU - Box,Matthew, AU - Johnström,Peter, AU - Varnäs,Katarina, AU - Malmquist,Jonas, AU - Thress,Kenneth S, AU - Jänne,Pasi A, AU - Cross,Darren, Y1 - 2016/07/19/ PY - 2016/02/12/received PY - 2016/07/05/accepted PY - 2016/7/21/pubmed PY - 2018/2/1/medline PY - 2016/7/21/entrez SP - 5130 EP - 5140 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 22 IS - 20 N2 - PURPOSE: Approximately one-third of patients with non-small cell lung cancer (NSCLC) harboring tumors with EGFR-tyrosine kinase inhibitor (TKI)-sensitizing mutations (EGFRm) experience disease progression during treatment due to brain metastases. Despite anecdotal reports of EGFR-TKIs providing benefit in some patients with EGFRm NSCLC brain metastases, there is a clinical need for novel EGFR-TKIs with improved efficacy against brain lesions. EXPERIMENTAL DESIGN: We performed preclinical assessments of brain penetration and activity of osimertinib (AZD9291), an oral, potent, irreversible EGFR-TKI selective for EGFRm and T790M resistance mutations, and other EGFR-TKIs in various animal models of EGFR-mutant NSCLC brain metastases. We also present case reports of previously treated patients with EGFRm-advanced NSCLC and brain metastases who received osimertinib in the phase I/II AURA study (NCT01802632). RESULTS: Osimertinib demonstrated greater penetration of the mouse blood-brain barrier than gefitinib, rociletinib (CO-1686), or afatinib, and at clinically relevant doses induced sustained tumor regression in an EGFRm PC9 mouse brain metastases model; rociletinib did not achieve tumor regression. Under positron emission tomography micro-dosing conditions, [11C]osimertinib showed markedly greater exposure in the cynomolgus monkey brain than [11C]rociletinib and [11C]gefitinib. Early clinical evidence of osimertinib activity in previously treated patients with EGFRm-advanced NSCLC and brain metastases is also reported. CONCLUSIONS: Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases. Further investigation of osimertinib in this patient population is ongoing. Clin Cancer Res; 22(20); 5130-40. ©2016 AACR. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/27435396/Preclinical_Comparison_of_Osimertinib_with_Other_EGFR_TKIs_in_EGFR_Mutant_NSCLC_Brain_Metastases_Models_and_Early_Evidence_of_Clinical_Brain_Metastases_Activity_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=27435396 DB - PRIME DP - Unbound Medicine ER -